Nicotine, (S)-3-(1-methyl-2-pyrrolidinyl)pyridine, is an alkaloid found mainly in tobacco. Smoking of tobacco results in nicotine dependence and is habit forming. Smoking has also been associated with disease of lungs including malignant growth. There is a world-wide recognition of harmful effects of smoking. Unfortunately habitual smokers find it very hard to achieve abstinence from smoking. Further dependence on nicotine comes in the way of any effort to control smoking. To overcome this formidable issue, products containing small amounts of nicotine have been developed and are being promoted as substitutes for traditional smoking products like cigars and cigarettes. Treating nicotine dependence requires therapeutic use of nicotine. Nicotine is given to patients through dermal patches, gums, creams, lozenges, nasal sprays or electric cigarettes to wean them away from smoking. Nicotine is also therapeutically used in treating certain medical conditions such as attention deficit disorder, Tourette's syndrome, schizophrenia, Alzheimer's disease, Parkinsonism etc.
The main source of nicotine is tobacco. Nicotine isolated from tobacco contains many related minor alkaloids as impurities in addition to impurities formed through degradation. European Pharmacopoeia monograph on nicotine prescribes limits for anatabine, anabasine, cotinine, myosmine, β-nicotyrine, nicotine-N-oxide and nornicotine impurities, with a maximum of 0.3% for each of these but total being limited to not more than 0.8%. British Pharmacopoeia also mentions anatabine, cotinine, myosmine, β-nicotyrine, nicotine-N-oxide as impurities. Although the USP does not mention specific impurities, a limit of 1% for all the impurities and not more than 0.5% for any one impurity is prescribed. The impurities present in natural nicotine vary depending on the geographical source of tobacco and the season in which it is collected. It is difficult to remove these impurities since they are closely related. Thus the pharmacopoeias recognize the variations in quality and quantity of impurities in natural nicotine.
It was envisaged that nicotine obtained from synthetic source will be free from the impurities present in natural nicotine. Further, synthetic nicotine produced by a validated process with well characterized impurity profile should be a superior API compared to natural nicotine with its varying impurity profile.
Several synthesis of (S)-nicotine are reported in the literature. Chiral center has been created by using expensive chiral intermediates such as prolinol (J. Org. Chem. 1982, 41, 1069-1073), pivaloyl-β-D-galactosylamine (Tetrahedron Letters, 1999, 40, 7847-7650), or using chiral catalyst (Synlett 2009, 9, 1413-1416). However, these methods are expensive and are not suitable for industrial production.